Antipsychotics and Progressive Brain Dysfunction

There are three main dopaminergic pathways in the brain. One involves the basal ganglia, which controls the initiation of motor movements. The second involves the limbic system, which is the area of the brain that helps us mount emotional responses to the world. The third is in the frontal lobes, which is the part of the brain that gives rise to self-consciousness.

Antipsychotics work by blocking dopamine receptors along these three pathways, and over the long-term, these pathways become increasingly dysfunctional (at least in a high percentage of patients.) The dysfunction in the basal ganglia leads to tardive dyskinesia. The dysfunction in the limbic system and the frontal lobes leads to tardive psychosis and tardive dementia.

With the old standard neuroleptics, tardive dyskinesia was found to appear in five percent of patients within one year of treatment, with the percentage so afflicted increasing an additional five percent with each additional year of exposure. The new atypicals like Zyprexa and Risperidone may pose less of a tardive risk, although this isn’t yet entirely clear.

Researchers have compared tardive dyskinesia to “known neurological diseases, such as Huntington’s disease, dystonia musculorum deformans, and postencephalitic brain damage.” Here are a handful of the studies that have documented this drug-caused brain dysfunction.


1. Tardive Dyskinesia in Patients Treated with Major Neuroleptics. Crane, G. American Journal of Psychiatry 124, supplement (1968):40-47.

2. Clinical Psychopharmacology in its 20th Year. Crane, G. Science181 (1973):124-128.

3. Functional Impairment in tardive dyskinesia. Yassa, R. Acta Psychiatrica Scandinavica80 (1989): 64-67.

4. Central Determinants of Attention and Mood Disorder in Tardive Dyskinesia.  Myslobodsky, M. Brain and Cognition 23 (1993):88-101.

5. Cognitive Dysfunction in Schizophrenia. Waddington, J. Brain and Cognition 23 (1993):56-70.

6.  The Effect of Atypical versus Typical Antipsychotics on TardiveDyskinesia. De Leon, J. Eur. Arch. Psychiatry Clinical Neurosciences 257 (2007):169-172.

Twenty percent of patients on atypicals developed tardive dyskinesia in less than five years, a rate similar to that with standard neuroleptics. Severe TD may even more of a problem with the atypicals than with the standard neuroleptics.

7. The Neuropathologic Effects of Antipsychotic Drugs. Harrison P. Schizophrenia Research 40 (1999):87-99.

A good review of the research literature documenting the many pathological effects of antipsychotic drugs.


Mad in America Documents

The evidence for antipsychotics

Antipsychotics and chronic illness

Antipsychotics and progressive brain dysfunction

Early death associated with antipsychotic drugs

Outcomes in the era of atypical antipsychotics

Modern experimental programs producing better outcomes

Timeline for antipsychotics



Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.


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